Nonarteritic anterior ischemic optic neuropathy (NAION) is one of the most common acute optic neuropathies that affect the over 55-year-old population. NAION causes the loss of visual function, and it has no safe and effective therapy. Bardoxolone methyl (methyl 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oate; CDDO-Me; RTA 402) is a semisynthetic triterpenoid with effects against antioxidative stress and inflammation in neurodegeneration and kidney disease that activates the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. Moreover, RTA 402 is an FDA-approved compound for the treatment of solid tumors, lymphoid malignancies, melanoma, and chronic kidney disease. Omaveloxolone (RTA 408) is an activator of Nrf2 and an inhibitor of NFκB, possessing antioxidative and anti-inflammatory activities in mitochondrial bioenergetics. RTA 408 is also under clinical investigation for Friedreich ataxia (FA). In this study, a rodent anterior ischemic optic neuropathy (rAION) model induced by photothrombosis was used to examine the therapeutic effects of RTA 402 and RTA 408. Treatment with RTA402 results in antiapoptotic, antioxidative stress, anti-inflammatory, and myelin-preserving effects on retinal ganglion cell (RGC) survival and visual function via regulation of NQO1 and HO-1, reduced IL-6 and Iba1 expression in macrophages, and promoted microglial expression of TGF-β and Ym1 + 2 in the retina and optic nerve. However, these effects were not observed after RTA 408 treatment. Our results provide explicit evidence that RTA 402 modulates the Nrf2 and NFκB signaling pathways to protect RGCs from apoptosis and maintain the visual function in an rAION model. These findings indicate that RTA 402 may a potential therapeutic agent for ischemic optic neuropathy.

中文翻译：

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两种 Nrf2 激活剂，甲基巴多索龙和奥马维洛酮，对缺血性视神经病变期间视网膜神经节细胞存活的影响

非动脉性前部缺血性视神经病变 (NAION) 是影响 55 岁以上人群的最常见的急性视神经病变之一。NAION导致视觉功能丧失，目前尚无安全有效的治疗方法。Bardoxolonemethyl（methyl 2-cyano-3,12-dioxoooleana-1,9(11)-dien-28-oate；CDDO-Me；RTA 402）是一种半合成的三萜，在神经变性和肾脏疾病中具有抗氧化应激和炎症作用激活核因子红细胞 2 相关因子 2 (Nrf2) 信号通路。此外，RTA 402 是 FDA 批准的化合物，用于治疗实体瘤、淋巴恶性肿瘤、黑色素瘤和慢性肾病。Omaveloxolone (RTA 408) 是 Nrf2 的激活剂和 NFκB 的抑制剂，在线粒体生物能量学中具有抗氧化和抗炎活性。RTA 408 也正在接受弗里德赖希共济失调 (FA) 的临床研究。在这项研究中，由光血栓形成引起的啮齿动物前部缺血性视神经病变 (rAION) 模型用于检查 RTA 402 和 RTA 408 的治疗效果。 RTA402 治疗导致抗细胞凋亡、抗氧化应激、抗炎和髓鞘保护作用通过调节 NQO1 和 HO-1 影响视网膜神经节细胞 (RGC) 存活和视觉功能，降低巨噬细胞中 IL-6 和 Iba1 的表达，并促进视网膜和视神经中小胶质细胞 TGF-β 和 Ym1 + 2 的表达。然而，在 RTA 408 处理后没有观察到这些影响。我们的结果提供了明确的证据，即 RTA 402 调节 Nrf2 和 NFκB 信号通路以保护 RGC 免受细胞凋亡并维持 rAION 模型中的视觉功能。